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Quantitative Structure-Antitumor Activity Relationships
of Camptothecin Analogues: Cluster Analysis and Genetic Algorithm-Based Studies
Fan Y, Shi LM, Kohn KW, Pommier Y, Weinstein JN.
J Med Chem 2001 Sep 27;44(20):3254-63
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Abstract: Topoisomerase 1 (top1) inhibitors are proving useful against a range of refractory tumors, and
there is considerable interest in the development of additional top1 agents. Despite crystallographic
studies, the binding site and ligand properties that lead to activity are poorly understood.
Here we report a unique approach to quantitative structure-activity relationship (QSAR) analysis
based on the National Cancer Institute's (NCI) drug databases. In 1990, the NCI established a
drug discovery program in which compounds are tested for their ability to inhibit the growth
of 60 different human cancer cell lines in culture. More than 70 000 compounds have been screened,
and patterns of activity against the 60 cell lines have been found to encode rich information
on mechanisms of drug action and drug resistance. Here, we use hierarchical clustering to
define antitumor activity patterns in a data set of 167 tested camptothecins (CPTs) in the
NCI drug database. The average pairwise Pearson correlation coefficient between activity patterns
for the CPT set was 0.70. Coherence between chemical structures and their activity patterns
was observed. QSAR studies were carried out using the mean 50% growth inhibitory concentrations
(GI(50)) for 60 cell lines as the dependent variables. Different statistical methods, including
stepwise linear regression, principal component regression (PCR), partial least-squares regression
(PLS), and fully cross-validated genetic function approximation (GFA) were applied to construct
quantitative structure-antitumor relationship models. For our data set, the GFA method performed
better in terms of correlation coefficients and cross-validation analysis. A number of molecular
descriptors were identified as being correlated with antitumor activity. Included were partial
atomic charges and three interatomic distances that define the relative spatial dispositions
of three significant atoms (the hydroxyl hydrogen of the E-ring, the lactone carbonyl oxygen
of the E-ring, and the carbonyl oxygen of the D-ring). The cross-validated r(2) for the final
GFA model was 0.783, indicating a predictive QSAR model.
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